A study by MIT and Mayo Clinic researchers published in the Célula journal finds that FTD and ALS have strikingly similar cellular and molecular characteristics despite their clinical differences.

The 2011 discovery that the C9orf72 gene mutation can cause FTD and/or ALS transformed the long-held belief that the two disorders were unrelated. It is now known that several other genes can cause both diseases, and that FTD and ALS can sometimes co-occur. As the authors note, 40-50% of people diagnosed with either disorder eventually develop symptoms of the other, with up to 15% receiving a dual diagnosis.

In the study, the authors theorized that ALS and FTD also shared genetic signatures. Although each disease targets unique cellular subtypes in different brain regions, recent research suggests that the affected neurons of both diseases share molecular markers. To test their theory, the authors conducted a specific form of RNA sequencing to generate data on the molecular structure of affected neurons.

Exceptional Gene-Level Similarity

The study was conducted on donated brain samples from 73 individuals. The sample cohort included those who had been diagnosed with FTD, ALS or showed no evidence of disease. The samples represented both people whose diagnosis was sporadic, meaning their FTD had no known genetic cause nor a known familial connection to neurodegenerative disease and those who had been impacted by the C9orf72 gene mutation.

According to the authors, their cohort included:

• 17 from donors with sporadic ALS.
• 16 from donors with C9orf72 ALS.
• 13 from donors with sporadic FTD.
• 11 from donors with C9orf72 FTD.
• 16 from donors without a diagnosis.

The authors found an “exceptional gene-level similarity” across neurons affected by both diseases. Examining the gene expression of neurons, the process through which cells convert genetic information to functional products like proteins, the researchers discovered that the affected neurons express remarkably similar genes. It was also noted that samples from inherited and sporadic cases of FTD and ALS showed similar genetic expression changes, contrasting with previous beliefs that they had different causes.

“These similarities were quite striking, suggesting that therapeutics for ALS may also apply to [FTD] and vice versa,” MIT researcher Myriam Heiman, PhD, the lead corresponding author of the study, told Noticias de neurociencia. “Our study can help guide therapeutic programs that would likely be effective for both diseases.”

Vulnerable Cells Share Expression Patterns

Looking past genetic expression, the authors scrutinized the more profoundly affected neurons. Von Economo neurons (VENs) are the most vulnerable cells in FTD, while upper motor neurons (UMNs) are the most vulnerable cells in ALS. Despite being in different locations of the brain, the genetic expression of the two types of neurons had very similar gene expression patterns.

“UMNs and spindle neurons look nothing alike and live in very different areas of the brain,” said MIT graduate student Sebastian Pineda, lead author of the study. “It was remarkable to see that they appear practically indistinguishable at the molecular level and respond very similarly to disease.”

The researchers noticed an association between many expressed genes and primary cilia, structures on the surface of cells that sense chemical changes. The authors identified almost 50 cilia-associated genes shared between the two diseases. It was further discovered that vulnerable cells expressed genes associated with FTD and ALS, hinting at a possible basis for the genetic association between the diseases.

The researchers also found evidence of cerebrovascular dysfunction complicated the blood-brain barrier (BBB), a filtering system that protects the brain from harmful molecules. Proteins necessary for maintaining brain vasculature were found to be misplaced or reduced in ALS. In FTD, the authors noticed a reduction in the protein HLA-E, which plays a role in regulating the immune system and is believed to help protect the BBB from degradation by immune responses.

The samples used in the study were provided after the donors had passed, meaning that the brain cells analyzed were the remaining survivors. As research advances, it may become possible for scientists to examine the genetic and molecular signatures of cells in people before the onset of FTD. Future studies could determine if there are unique signatures in the cells that degenerate in FTD and ALS that can be detected early.

Scientists are increasingly studying the links between ALS and FTD to find new ways to diagnose and treat both disorders. Researchers at the University of Sheffield in the United Kingdom discovered in a study published in early 2024 on how to prevent the production of toxic proteins associated with FTD and ALS.

Are you interested in participating in research studies furthering our understanding of FTD? The Registro de trastornos de FTD makes it easy for families to stay up to date on the latest opportunities to participate in research while providing the opportunity to share lived experiences directly with researchers.